1. Name of the medicinal product
Co-Trimoxazole Tablets BP 80mg/400mg Taj Pharma
Co-Trimoxazole Tablets BP 160mg/800mg Taj Pharma

2. Qualitative and quantitative composition
a) Co-Trimoxazole Tablets BP 80mg/400mg Taj Pharma
Each uncoated tablet contains:
Trimethoprim BP 80mg
Sulfamethoxazole BP 400mg
Excipients: Q.S.

b) Co-Trimoxazole Tablets BP 160mg/800mg Taj Pharma
Each uncoated tablet contains:
Trimethoprim BP 160mg
Sulfamethoxazole BP 800mg
Excipients: Q.S.

For a full list of excipients, see section 6.1

3. Pharmaceutical form

Uncoated Tablets,

Co-trimoxazole Taj Pharma tablets are white, circular, biconvex uncoated tablets.

  1. Clinical particulars

Therapeutic indications

Co-Trimoxazole Taj Pharma is indicated in adults and children (>12 to <18 years old) and adults (>18 years old).

Co-Trimoxazole Taj Pharma tablets are indicated for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

  • Treatment and prevention of Pneumocystis jiroveci pneumonitis or ‘PJP’.
  • Treatment and prophylaxis of toxoplasmosis
  • Treatment of nocardiosis.

The following infections may be treated with Co-Trimoxazole Taj Pharma where there is bacterial evidence of sensitivity to Co-Trimoxazole Taj Pharma and good reason to prefer the combination of antibiotics in Co-Trimoxazole Taj Pharma to a single antibiotic:

  • Acute uncomplicated urinary tract infection
  • Acute otitis media
  • Acute exacerbation of chronic bronchitis

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

  • Posology and method of administration

Posology

General Dosage Recommendations

Where dosage is expressed as “tablets” this refers to the adult tablet, i.e. 80 mg Trimethoprim BP and 400 mg Sulfamethoxazole BP. If other formulations are to be used appropriate adjustment should be made.

Standard dosage recommendations for acute infections

Adults (>18 years old):

STANDARD DOSAGE
AgeTablets
>18 years old2 tablets every 12 hours

Children over 12 years old (>12 to <18 years old):

The standard dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg body weight per day, given in two equally divided doses. The schedules for children are according to the child’s age and provided in the table below:

AgeTablets
>12 to <18 years old2 tablets every 12 hours

Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least 5 days. If clinical improvement is not evident after 7 days therapy, the patient should be reassessed.

As an alternative to Standard Dosage for acute uncomplicated lower urinary tract infections, short-term therapy of 1 to 3 days duration has been shown to be effective.

Elderly patients:

See Special Warnings and Precautions for Use (Section 4.4). Unless otherwise specified standard dosage applies.

Impaired hepatic function:

No data are available relating to dosage in patients with impaired hepatic function.

Impaired renal function:

Dosage recommendation:

Children (>12 to <18 years old) and adults (>18 years old):

Creatinine Clearance (ml/min)Recommended Dosage
>302 tablets every 12 hours
15 to 301 tablets every 12 hours
<15Not recommended

No information available for children aged 12 years and under with renal failure. See section 5.2 for the pharmacokinetics in the paediatric population with normal renal function of both components of Co-Trimoxazole, TMP and SMZ.

Measurements of plasma concentration of sulfamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of Co-Trimoxazole. If the concentration of total sulfamethoxazole exceeds 150 microgram/ml then treatment should be interrupted until the value falls below 120 microgram/ml.

Pneumocystis jirovecii pneumonitis

Treatment – Children (>12 to <18 years old) and adults (>18 years old):

A higher dosage is recommended, using 20 mg trimethoprim and 100 mg sulfamethoxazole per kg of body weight per day in two or more divided doses for two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous Co-Trimoxazole). (See 4.8 Undesirable Effects).

Prevention – Adults (>18 years old):

The following dose schedules may be used:

160 mg trimethoprim/800 mg sulfamethoxazole daily 7 days per week.

160 mg trimethoprim/800 mg sulfamethoxazole three times per week on alternate days.

320 mg trimethoprim/1600 mg sulfamethoxazole per day in two divided doses three times per week on alternate days.

Prevention – Children (>12 to <18 years old):

The standard dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg body weight per day, given in two equally divided doses. The following dose schedules may be used for the duration of the period at risk:

AgeTablets
>12 to <18 years old2 tablets every 12 hours, seven days per week
>12 to <18 years old2 tablets every 12 hours, three times per week on alternative days
>12 to <18 years old2 tablets every 12 hours, three times per week on consecutive days
>12 to <18 years old4 tablets once a day, three times per week on consecutive days

The daily dose given on a treatment day approximates to 150 mg trimethoprim/m2/day and 750 mg sulfamethoxazole/m2/day. The total daily dose should not exceed 320 mg trimethoprim and 1600 mg sulfamethoxazole.

Nocardiosis – Adults (>18 years old):

There is no consensus on the most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used.

Toxoplasmosis:

There is no consensus on the most appropriate dosage for the treatment or prophylaxis of this condition. The decision should be based on clinical experience. For prophylaxis, however, the dosages suggested for prevention of Pneumocystis jirovecii pneumonitis may be appropriate.

Method of administration: Oral.

It may be preferable to take Co-Trimoxazole Taj Pharma with some food or drink to minimise the possibility of gastrointestinal disturbances.

  • Contraindications
  • Hypersensitivity to the active substance, sulphonamides, trimethoprim, Co-Trimoxazole Taj Pharma or to any of the excipients listed in section 6.1.
  • Contra-indicated in patients showing marked severe liver parenchymal damage.
  • Contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.
  • Co-Trimoxazole Taj Pharma should not be given to infants during the first 6 weeks of life.
  • Co-Trimoxazole Taj Pharma should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides.
  • Co-Trimoxazole Taj Pharma should not be given to patients with acute porphyria.
    • Special warnings and precautions for use

Fatalities, although very rare, have occurred due to severe reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.

  • Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of co-trimoxazole.
  • Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS, TEN or DRESS is within the first weeks of treatment.
  • If symptoms or signs of SJS, TEN or DRESS (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Co-Trimoxazole Taj Pharma treatment should be discontinued (see 4.8 Undesirable Effects).
  • The best results in managing SJS, TEN and DRESS come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.
  • If the patient has developed SJS or TEN with the use of co-trimoxazole, Co-Trimoxazole Taj Pharma must not be re-started in this patient at any time.

Particular care is always advisable when treating elderly patients because, as a group, they are more susceptible to adverse reactions and more likely to suffer serious effects as a result particularly when complicating conditions exist, e.g. impaired kidney and/or liver function and/or concomitant use of other drugs.

For patients with known renal impairment special measures should be adopted (see section 4.2).

An adequate urinary output should be maintained at all times. Evidence of crystalluria in vivo is rare, although sulfonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition the risk may be increased.

Regular monthly blood counts are advisable when Co-Trimoxazole Taj Pharma is given for long periods, or to folate deficient patients or to the elderly; since there exists a possibility of asymptomatic changes in haematological laboratory indices due to lack of available folate. Supplementation with folinic acid may be considered during treatment but this should be initiated with caution due to possible interference with antimicrobial efficacy (see section 4.5).

In glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients haemolysis may occur.

Co-Trimoxazole Taj Pharma should be given with caution to patients with severe allergy or bronchial asthma.

Co-Trimoxazole Taj Pharma should not be used in the treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci; eradication of these organisms from the oropharynx is less effective than with penicillin.

Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

The administration of Co-Trimoxazole Taj Pharma to patients known or suspected to be at risk of acute porphyria should be avoided. Both trimethoprim and sulfonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.

Close monitoring of serum potassium is warranted in patients at risk of hyperkalaemia.

Co-Trimoxazole Taj Pharma has been associated with metabolic acidosis when other possible underlying causes have been excluded. Close monitoring is always advisable when metabolic acidosis is suspected.

Except under careful supervision Co-Trimoxazole Taj Pharma should not be given to patients with serious haematological disorders (see 4.8 Undesirable Effects). Co-Trimoxazole Taj Pharma has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

The combination of antibiotics in Co-Trimoxazole Taj Pharma should only be used where, in the judgement of the physician, the benefits of treatment outweigh any possible risks; consideration should be given to the use of a single effective antibacterial agent.

Concomitant use of medicinal products known to cause hyperkalaemia with Co-Trimoxazole Taj Pharma may result in severe hyperkalaemia.

  • Interaction with other medicinal products and other forms of interaction

Interaction with laboratory tests: trimethoprim may interfere with the estimation of serum/plasma creatinine when the alkaline picrate reaction is used. This may result in overestimation of serum/plasma creatinine of the order of 10%. The creatinine clearance is reduced: the renal tubular secretion of creatinine is decreased from 23% to 9% whilst the glomerular filtration remains unchanged.

Zidovudine: in some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to co-trimoxazole. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.

Cyclosporin: reversible deterioration in renal function has been observed in patients treated with Co-Trimoxazole Taj Pharma and cyclosporin following renal transplantation.

Rifampicin: concurrent use of rifampicin and Co-Trimoxazole Taj Pharma results in a shortening of the plasma half-life of trimethoprim after a period of about one week. This is not thought to be of clinical significance.

When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.

Diuretics (thiazides): in elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

Pyrimethamine: occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co- trimoxazole be prescribed concurrently.

Warfarin: Co-Trimoxazole Taj Pharma has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Co-Trimoxazole Taj Pharma is advisable.

Phenytoin: Co-Trimoxazole Taj Pharma prolongs the half-life of phenytoin and if co-administered could result in excessive phenytoin effect. Close monitoring of the patient’s condition and serum phenytoin levels are advisable.

Digoxin: concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients.

Methotrexate: Co-Trimoxazole Taj Pharma may increase the free plasma levels of methotrexate. If Co-Trimoxazole Taj Pharma is considered appropriate therapy in patients receiving other anti- folate drugs such as methotrexate, a folate supplement should be considered (see section 4.4).

Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.

Lamivudine: administration of trimethoprim /sulfamethoxazole 160 mg/800 mg (co- trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.

Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.

Hyperkalaemia: caution should be exercised in patients taking any other drugs that can cause hyperkalaemia, for example ACE inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone. Concomitant use of trimethoprim-sulfamethoxazole (co-trimoxazole) may result in clinically relevant hyperkalaemia.

Repaglinide: trimethoprim may increase the exposure of repaglinide which may result in hypoglycaemia.

Folinic acid: folinic acid supplementation has been shown to interfere with the antimicrobial efficacy of trimethoprim-sulfamethoxazole. This has been observed in Pneumocystis jirovecii pneumonia prophylaxis and treatment.

Contraceptives: oral contraceptive failures have been reported with antibiotics. The mechanism of this effect has not been elucidated. Women on treatment with antibiotics should temporarily use a barrier method in addition to the oral contraceptive, or choose another method of contraception.

Azathioprine: There are conflicting clinical reports of interactions between azathioprine and trimethoprim-sulfamethoxazole, resulting in serious haematological abnormalities.

  • Fertility, pregnancy and lactation

Pregnancy

Trimethoprim and sulfamethoxazole cross the placenta and their safety in pregnant women has not been established. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans.

Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities (see section 5.3).

Co-Trimoxazole Taj Pharma should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Co-Trimoxazole Taj Pharma is used in pregnancy.

Sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when Co-Trimoxazole Taj Pharma is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency.

Breast-feeding

The components of Co-Trimoxazole Taj Pharma (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of Co-Trimoxazole Taj Pharma should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia. Additionally, administration of Co-Trimoxazole Taj Pharma should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.

  • Effects on ability to drive and use machines

There have been no studies to investigate the effect of Co-Trimoxazole Taj Pharma on driving performance or the ability to operate machinery. Further a detrimental effect on such activities cannot be predicted from the pharmacology of the drug. Nevertheless the clinical status of the patient and the adverse events profile of Co-Trimoxazole Taj Pharma should be borne in mind when considering the patients ability to operate machinery.

  • Undesirable effects

The frequency categories associated with the adverse events below are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication.

Data from large published clinical trials were used to determine the frequency of very common to rare adverse events. Very rare adverse events were primarily determined from post-marketing experience data and therefore refer to reporting rate rather than a “true” frequency.

The following convention has been used for the classification of adverse events in terms of frequency: Very common ≥1/10, common ≥1/100 and <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000, not known – cannot be estimated from the available data.

System Organ ClassFrequencySide effects
Infections and infestationsCommonOvergrowth fungal.
Very rarePseudomembranous colitis
Blood and lymphatic system disordersVery rareLeukopenia, neutropenia, thrombocytopenia, agranulocytosis, anaemia megaloblastic, aplastic anaemia, haemolytic anaemia, methaemoglobinaemia, eosinophilia, purpura, haemolysis in certain susceptible G-6-PD deficient patients.
Immune system disordersVery rareSerum sickness, anaphylactic reaction, allergic myocarditis, hypersensitivity vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus.

Severe hypersensitivity reactions associated with PJP*, rash, pyrexia, neutropenia, thrombocytopenia, hepatic enzyme increased, hyperkalaemia, hyponatraemia, rhabdomyolysis.

Metabolism and nutrition disordersVery commonHyperkalaemia.
Very rareHypoglycaemia, hyponatraemia, decreased appetite, metabolic acidosis
Psychiatric disordersVery rareDepression, hallucination.
Not knownPsychotic disorder.
Nervous system disordersCommonHeadache.
Very rareMeningitis aseptic *, convulsions, neuropathy peripheral, ataxia, dizziness.
Ear and labrynth disordersVery rareVertigo, tinnitus
Eye disordersVery rareUveitis
Respiratory, thoracic and mediastinal disordersVery rareCough *, dyspnoea*, lung infiltration*.
Gastrointestinal disordersCommonNausea, diarrhoea.
UncommonVomiting.
Very rareGlossitis, stomatitis, pancreatitis.
Hepatobiliary disordersVery rareTransaminases increased, blood bilirubin increased, cholestatic jaundice, hepatic necrosis
Skin and subcutaneous tissue disorders*CommonRash
Very rarePhotosensitivity reaction, angiodema, dermatitis exfoliative, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome (SJS) *, toxic epidermal necrolysis (TEN) *.
Not knownDrug reaction with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disordersVery rareArthralgia, myalgia.
Renal and urinary disordersVery rareRenal impairment (sometimes reported as renal failure), tubulointerstitial nephritis and uveitis syndrome, renal tubular acidosis

* see description of selected adverse reactions

Description of selected adverse reactions

Aseptic meningitis

Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either Co-Trimoxazole Taj Pharma or to trimethoprim alone.

The majority of haematological changes are mild and reversible when treatment is stopped. Most of the changes cause no clinical symptoms although they may become severe in isolated cases, especially in the elderly, in those with hepatic or renal dysfunction or in those with poor folate status. Fatalities have been recorded in at-risk patients and these patients should be observed carefully (see 4.3 Contra-indications).

Close supervision is recommended when Co-Trimoxazole Taj Pharma is used in elderly patients or in patients taking high doses of Co-Trimoxazole Taj Pharma as these patients may be more susceptible to hyperkalaemia and hyponatraemia.

Pulmonary hypersensitivity reactions

Cough, dyspnoea and lung infiltration may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.

Hepatobiliary disorders

Jaundice cholestatic and hepatic necrosis may be fatal.

Severe cutaneous adverse reactions (SCARs)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4).

Effects associated with Pneumocystis jirovecii Pneumonitis (PJP) management.

Very rare: Severe hypersensitivity reactions, rash, pyrexia, neutropenia, thrombocytopenia, hepatic enzyme increased, hyperkalaemia, hyponatraemia, rhabdomyolysis.

At the high dosages used for PJP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. If signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5-10 mg/day). Severe hypersensitivity reactions have been reported in PJP patients on re-exposure to co-trimoxazole, sometimes after a dosage interval of a few days.

Rhabdomyolysis has been reported in HIV positive patients receiving trimethoprim-sulfamethoxazole for prophylaxis or treatment of PJP.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Overdose

Symptoms

Nausea, vomiting, dizziness and confusion are likely signs/symptoms of overdosage. Bone marrow depression has been reported in acute trimethoprim overdosage.

Treatment

If vomiting has not occurred, induction of vomiting may be desirable. Gastric lavage may be useful, though absorption from the gastrointestinal tract is normally very rapid and complete within approximately two hours. This may not be the case in gross overdosage. Dependant on the status of renal function administration of fluids is recommended if urine output is low.

Both trimethoprim and active sulfamethoxazole are moderately dialysable by haemodialysis. Peritoneal dialysis is not effective.

  1. Pharmacological properties
    • Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of sulfonamides and trimethoprim, incl. derivatives;

Mechanism of Action

Co-Trimoxazole Taj Pharma is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. Sulfamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme active in the folate metabolic pathway converting dihydrofolate to tetrahydrofolate.Depending on the conditions the effect may be bactericidal. Thus trimethoprim and sulfamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.

Trimethoprim binds to plasmodial DHFR but less tightly than to the bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

Mechanism of resistance

In vitro studies have shown that bacterial resistance can develop more slowly with both sulfamethoxazole and trimethoprim in combination that with either sulfamethoxazole or trimethoprim alone.

Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out-compete with sulfamethoxazole resulting in a reduction of the inhibitory effect on dihydropteroate synthetase enzyme. Another resistance mechanism is plasmid-mediated and results from production of an altered dihydropteroate synthetase enzyme, with reduced affinity for sulfamethoxazole compared to the wild-type enzyme.

Resistance to trimethoprim occurs through a plasmid-mediated mutation which results in production of an altered dihydrofolate reductase enzyme having a reduced affinity for trimethoprim compared to the wild-type enzyme.

Trimethoprim binds to plasmodial DHFR but less tightly than to bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

Many common pathogenic bacteria are susceptible in vitro to trimethoprim and sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antibiotics, however, in vitro activity does not necessarily imply that clinical efficacy has been demonstrated and it must be noted that satisfactory susceptibility testing is achieved only with recommended media free from inhibitory substances, especially thymidine and thymine.

Susceptability testing breakpoints

EUCAST

Enterobacteriaceae: S≤ 2 R> 4

  1. maltophilia: S≤ 4 R> 4

Acinetobacter: S≤ 2 R> 4

Staphylococcus: S≤ 2 R> 4

Enterococcus: S≤ 0.032 R> 1

Streptococcus ABCG: S≤ 1 R> 2

Streptococcus pneumoniae: S≤ 1 R> 2

Hemophilus influenza: S≤ 0.5 R> 1

Moraxella catarrhalis: S≤0.5 R >1

Psuedomonas aeruginosa and other non-enterobacteriaceae: S≤ 2* R> 4*

S = susceptible, R = resistant. *These are CLSI breakpoints since no EUCAST breakpoints are currently available for these organisms.

Trimethoprim: sulfamethoxazole in the ratio 1:19. Breakpoints are expressed as trimethoprim concentration.

Antibacterial Spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to trimethoprim/sulfamethoxazole or not.

Trimethoprim/sulfamethoxazole susceptibility against a number of bacteria are shown in the table below:

Commonly susceptible species:
Gram-positive aerobes:

Staphylococcus aureus

Staphylococcus saprophyticus

Streptococcus pyogenes

Gram-negative aerobes:

Enterobacter cloacae

Haemophilus influenzae

Klebsiella oxytoca

Moraxella catarrhalis

Salmonella

spp.

Stenotrophomonas maltophilia

Yersinia spp.

Species for which acquired resistance may be a problem:
Gram-positive aerobes:

Enterococcus faecalis

Enterococcus faecium

Nocardia

spp.

Staphylococcus epidermidis

Streptococcus pneumoniae

Gram-negative aerobes:

Citrobacter spp.

Enterobacter aerogenes

Escherichia coli

Klebsiella pneumoniae

Klebsiella pneumonia

Proteus mirabilis

Proteus vulgaris

Providencia spp.

Serratia marcesans

Inherently resistant organisms:
Gram-negative aerobes:

Pseudomonas aeruginosa

Shigella spp.

Vibrio cholera

Pharmacokinetic properties

Absorption

After oral administration trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed. The presence of food does not appear to delay absorption. Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Effective levels persist in the blood for up to 24 hours after a therapeutic dose. Steady state levels in adults are reached after dosing for 2-3 days. Neither component has an appreciable effect on the concentrations achieved in the blood by the other.

Distribution

Approximately 50% of trimethoprim in the plasma is protein bound.

Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, saliva, sputum and vaginal secretions. Levels in the aqueous humor, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (intestinal) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and foetal tissues reaching concentrations approximating those of maternal serum.

Approximately 66% of sulfamethoxazole in the plasma is protein bound. The concentration of active sulfamethoxazole in amniotic fluid, aqueous humour, bile, cerebrospinal fluid, middle ear fluid, sputum, synovial fluid and tissue (interstitial) fluids is of the order of 20 to 50% of the plasma concentration.

Biotransformation

Renal excretion of intact sulfamethoxazole accounts for 15-30% of the dose. This drug is more extensively metabolised than trimethoprim, via acetylation, oxidation or glucuronidation. Over a 72 hour period, approximately 85% of the dose can be accounted for in the urine as unchanged drug plus the major (N4-acetylated) metabolite.

Elimination

The half-life of trimethoprim in man is in the range 8.6 to 17 hours in the presence of normal renal function. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10 ml/minute. There appears to be no significant difference in elderly patients compared with young patients.

The principal route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely.

The half-life of sulfamethoxazole in man is approximately 9 to 11 hours in the presence of normal renal function.

There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 ml /minute.

The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form.

The pharmacokinetics in the paediatric population with normal renal function of both components of Co-Trimoxazole, TMP and SMZ are age dependent. Elimination of TMP-SMZ is reduced in neonates, during the first two months of life; thereafter both TMP and SMZ show a higher elimination with a higher body clearance and a shorter elimination half-life. The differences are most prominent in young infants (> 1.7 months up to 24 months) and decrease with increasing age, as compared to young children (1 year up to 3.6 years), children (7.5 years and < 10 years) and adults (see section 4.2).

Trimethoprim is a weak base with a pKa of 7.4. It is lipophilic. Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, saliva, sputum and vaginal secretions. Levels in the aqueous humor, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (intestinal) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and foetal tissues reaching concentrations approximating those of maternal serum.

In elderly patients there is a reduced renal clearance of sulfamethoxazole.

Special patient population

Renal impairment

The elimination half-life of trimethoprim is increased by a factor of 1.5-3.0 when the creatinine clearance is less than 10 mL/minute. When the creatinine clearance falls below 30 mL/min the dosage of Co-Trimoxazole Taj Pharma should be reduced (see section 4.2).

Hepatic impairment

Caution should be exercised when treating patients with severe hepatic parenchymal damage as there may be changes in the absorption and biotransformation of trimethoprim and sulfamethoxazole.

Elderly patients

In elderly patients, a slight reduction in renal clearance of sulfamethoxazole but not trimethoprim has been observed.

Paediatric population

See special dosage regimen (see section 4.2).

Preclinical safety data

Reproductive toxicology: At doses in excess of recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats, findings typical of a folate antagonist. Effects with trimethoprim were preventable by administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses.

  1. Pharmaceutical particulars

List of excipients

Also contains: docusate sodium, magnesium stearate, maize starch, silica, sodium lauryl sulfate, stearic acid, industrial methylated spirit.

Incompatibilities

None known.

Shelf life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

  • Special precautions for storage

Store below 25°C in a dry place.
Protect from light.

  • Nature and contents of container

The product may also be supplied in blister packs in cartons:

Pack size:  14, 28, 56, 60, 100, 200 and 300 or 500 tablets.

Maximum size of bulk packs: 500

Not all pack size may be marketed

  • Special precautions for disposal and other handling

Not applicable.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Co-trimoxazole tablets BP and 160mg/800mg Taj Pharma

 (Trimethoprim and Sulfamethoxazole)

Package leaflet: Information for the patient

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist.
  • This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Co-trimoxazole Taj Pharma tablets are and what they are used for
  2. What you need to know before you take Co-trimoxazole Taj Pharma tablets
  3. How to take Co-trimoxazole Taj Pharma tablets
  4. Possible side effects
  5. How to store Co-trimoxazole Taj Pharma tablets
  6. Contents of the pack and other information

1. What Co-trimoxazole Taj Pharma tablets are and what they are used for

Co-trimoxazole Taj Pharma 80 mg/400 mg Tablets (called ‘Co-trimoxazole Taj Pharma tablets’ in this leaflet) are made up of two different medicines called sulfamethoxazole and trimethoprim. Both belong to a group of medicines called antibiotics. They are used to treat infections caused by bacteria. Like all antibiotics, Co-trimoxazole Taj Pharma only works against some types of bacteria. This means that it is only suitable for treating some types of infections.

Co-trimoxazole Taj Pharma tablets are used for adults and children over 12 years.

Co-trimoxazole Taj Pharma tablets can be used to treat or prevent:

  • lung infections (pneumonia or PCP) caused by a bacteria called Pneumocystis jiroveci
  • infections caused by a bacteria called Toxoplasma (toxoplasmosis).

Co-trimoxazole Taj Pharma tablets can be used to treat:

  • bladder or urinary tract infections (water infections)
  • lung infections such as bronchitis
  • ear infections such as otitis media
  • an infection called nocardiosis, it can affect the lungs, skin and brain.
  1. What you need to know before you take Co-trimoxazole Taj Pharma tablets

Do not take Co-trimoxazole Taj Pharma tablets if:

  • you are allergic (hypersensitive) to sulfamethoxazole, trimethoprim or Co-trimoxazole Taj Pharma or any of the other ingredients of Co-trimoxazole Taj Pharma tablets (see section 6)
  • you are allergic to sulfonamide medicines. Examples include sulfonylureas (such as gliclazide and glibenclamide) or thiazide diuretics (such as bendroflumethiazide – a water tablet)
  • you have liver or kidney problems
  • you have ever had a problem with your blood causing bruises or bleeding (thrombocytopenia)
  • you have been told that you have a rare blood problem called porphyria, which can affect your skin or nervous system
  • Co-trimoxazole Taj Pharma should not be given to infants during the first 6 weeks of life.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Co-trimoxazole Taj Pharma tablets.

Warnings and precautions:

Talk to your doctor or pharmacist before taking Co-trimoxazole Taj Pharma if:

  • you have severe allergies or asthma
  • you have been told that you have a rare blood problem called porphyria, which can affect your skin or nervous system
  • You don’t have enough folic acid (a vitamin) in your body – which can make your skin pale and make you feel tired, weak and breathless. This is known as anaemia
  • you have ever had jaundice which can cause yellowing of your skin or the whites of your eyes
  • you have a problem with your metabolism called phenylketonuria and are not on a special diet to help your condition
  • you are elderly
  • you have a kidney disease
  • you are underweight or malnourished
  • you have been told by your doctor that you have a lot of potassium in your blood. Concomitant administration of Co-trimoxazole Taj Pharma tablets with certain medicines, potassium supplements and food rich in potassium may lead to severe hyperkalaemia (increased potassium blood level). The symptoms of severe hyperkalaemia might include muscle cramps, irregular heart rhythm, diarrhoea, nausea, dizziness or headache.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Co-trimoxazole Taj Pharma tablets.

Skin reactions – if you develop a rash or any of the following symptoms, seek immediate advice from a doctor and tell them that you are taking this medicine:

  • potentially life-threatening skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS)) have been reported with the use of Co-trimoxazole Taj Pharma appearing initially as reddish target-like spots or circular patches often with central blisters on the trunk. If you have developed Stevens-Johnson syndrome, toxic epidermal necrolysis or DRESS with the use of Cotrimoxazole tablets you must not be re-started on Co-trimoxazole Taj Pharma tablets at any time
  • additional signs to look for include ulcers in the mouth, throat, nose, genitals and conjunctivitis (red and swollen eyes)
  • These potentially life-threatening skin rashes are often accompanied by flu-like symptoms. The rash may progress to widespread blistering or peeling of the skin
  • The highest risk for occurrence of serious skin reactions is within the first weeks of treatment.

Other medicines and Co-trimoxazole Taj Pharma

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

This includes herbal medicines. This is because Co-trimoxazole Taj Pharma tablets can affect the way some medicines work. Also some other medicines can affect the way Co-trimoxazole Taj Pharma tablets work.

  • Diuretics (water tablets) such as spironolactone, which help increase the amount of urine you produce
  • Pyrimethamine, used to treat and prevent malaria, and to treat diarrhoea
  • Ciclosporin, used after organ transplant surgeries
  • Blood thinners such as warfarin
  • Phenytoin, used to treat epilepsy (fits)
  • Medicines used to treat diabetes, such as glibenclamide, glipizide or tolbutamide (sulphonylureas) and repaglinide
  • Rifampicin, an antibiotic
  • Medicines to treat problems with the way your heartbeats such as digoxin or procainamide
  • Amantadine, used to treat Parkinson’s disease, multiple sclerosis, ‘flu’ or shingles
  • Medicines to treat HIV (Human Immunodeficiency Virus), called zidovudine or lamivudine
  • Medicines that can increase the amount of potassium in your blood, such as diuretics (water tablets, which help increase the amount of urine you produce, such as spironolactone), steroids (like prednisolone), digoxin
  • Methotrexate, a medicine used to treat certain cancers or certain diseases affecting your immune system
  • Folinic acid
  • Contraceptive medicines.

Co-trimoxazole Taj Pharma tablets with food and drink

You should take Co-trimoxazole Taj Pharma tablets with some food or drink. This will stop you feeling sick (nausea) or having diarrhoea. Although it is better to take them with food, you can still take them on an empty stomach.

Drink plenty of fluid such as water while you are taking Co-trimoxazole Taj Pharma tablets.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

  1. How to take Co-trimoxazole Taj Pharma tablets

Always take this medicine exactly as described in this leaflet or as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is:

AdultsSTANDARD DOSAGE
AgeTablets
>18 years old2 Tablets every 12 hours

Children over 12 years

The schedules for children are according to the child’s age and body weight provided in the table below:

>12 years and overOR>Weighing 53 kg or aboveTwo tablets in a morning and two tablets in an evening
  • Co-trimoxazole Taj Pharma should be taken for at least five days.
  • Make sure that you finish the course of Co-trimoxazole Taj Pharma which your doctor has prescribed.

Co-trimoxazole Taj Pharma 80mg/400mg tablets are not usually given to children under 12 years old. If they have been given to your child under 12 years please speak to your doctor or pharmacist for more information.

Special Dose

The dose of Co-trimoxazole Taj Pharma tablets and how long you need to take it depends on the infection you have and how bad it is. Your doctor may prescribe you a different dose or length of course of Co-trimoxazole Taj Pharma to:

  • treat urinary tract (water) infections
  • treat and prevent lung infections caused by the bacteria Pneumocystis jiroveci
  • Treat infections caused by the bacteria Toxoplasma (toxoplasmosis) or Nocardia (nocardiosis).

If you have kidney problems your doctor may:

  • prescribe a lower dose of Co-trimoxazole Taj Pharma tablets
  • Take blood to test whether the medicine is working properly.

If you take Co-trimoxazole Taj Pharma tablets for a long time your doctor may:

  • take blood to test whether the medicine is working properly
  • Prescribe folic acid (a vitamin) for you to take at the same time as Co-trimoxazole Taj Pharma tablets.

If you take more Co-trimoxazole Taj Pharma tablets than you should

If you take more Co-trimoxazole Taj Pharma tablets than you should, talk to your doctor or go to a hospital straight away. Take the medicine pack with you. If you have taken too many Co-trimoxazole Taj Pharma  tablets you may:

  • feel or be sick
  • feel dizzy or confused.

If you forget to take Co-trimoxazole Taj Pharma tablets

If you forget to take a dose, take it as soon as you remember it. Do not take a double dose to make up for the forgotten dose.

  1. Possible side effects

Like all medicines, this medicine can cause side-effects, although not everybody gets them.

Stop taking Co-trimoxazole Taj Pharma tablets and tell your doctor immediately if you have an allergic reaction. Chances of an allergic reaction is very rare (may affect up to 1 in 10,000 people), signs of an allergic reaction include:

  • Difficulty in breathing
  • Fainting
  • Swelling of face
  • Swelling of mouth, tongue or throat which may be red and painful and/or cause difficulty in swallowing
  • Chest pain
  • Red patches on the skin.

Tell your doctor if you notice any of the following side effects or notice any other effects not listed:

Very Common (may affect more than 1 in 10 people)

  • Excessive potassium in the blood (may occur as muscle cramps or pain, irregular heartbeats, unusual tiredness or weakness).

Common (may affect up to 1 in 10 people)

  • An infection called thrush or candidiasis which can affect your mouth or vagina. It is caused by a fungus
  • Headache
  • Feeling sick (nausea)
  • Diarrhoea
  • Skin rashes

Uncommon (may affect up to 1 in 100 people)

  • Being sick (vomiting).

Very Rare (may affect up to 1 in 10,000 people)

  • Fever (high temperature) or frequent infections
  • Sudden wheeziness or difficulty breathing
  • Potentially life-threatening skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported (see Take special care with Co-trimoxazole Taj Pharma tablets)
  • Mouth ulcers, cold sores and ulcers or soreness of your tongue
  • Skin lumps or hives (raised, red or white, itchy patches of skin)
  • Blisters on your skin or inside your mouth, nose, vagina or bottom
  • Inflammation of the eye which causes pain and redness
  • The appearance of a rash or sunburn when you have been outside (even on a cloudy day)
  • Low levels of sodium in your blood
  • Changes in blood tests
  • Feeling weak, tired or listless, pale skin (anaemia)
  • Heart problems
  • Jaundice (the skin and the whites of your eyes turn yellow). This can occur at the same time as unexpected bleeding or bruising
  • Pains in your stomach, which can occur with blood in your faeces (poo)
  • Pains in your chest, muscles or joints and muscle weakness
  • Arthritis
  • Problems with your urine. Difficulty passing urine. Passing more or less urine than usual. Blood or cloudiness in your urine
  • Kidney problems
  • Sudden headache or stiffness of your neck, accompanied by fever (high temperature)
  • Problems controlling your movements
  • Fits (convulsions or seizures)
  • Feeling unsteady or giddy
  • Ringing or other unusual sounds in your ears
  • Tingling or numbness in your hands and feet
  • Seeing strange or unusual sights (hallucinations)
  • Depression
  • Muscle pain and/or muscle weakness in HIV patients
  • Loss of appetite
  • Cough
  • Abnormal chemical levels in the blood (e.g. of potassium, sodium, calcium, urea).

Not Known (frequency cannot be estimated from the available data)

  • Drug reaction with eosinophilia and systemic symptoms (DRESS)
  • Psychotic disorder (a mental state in which you may lose touch with reality).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store Co-trimoxazole Taj Pharma tablets

Keep this medicine out of the sight and reach of children.

Store below 25ºC in a dry place and protect from light. Do not use Co-trimoxazole Taj Pharma tablets after the expiry date stated on the label/ carton/bottle. The expiry date refers to the last day of that month.

Do not throw away any medicine via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

What Co-trimoxazole Taj Pharma tablets contain

  • The active substances (the ingredients that make the tablets work) are 80mg of trimethoprim and 400mg of sulfamethoxazole.
  • The other ingredients are docusate sodium, magnesium stearate, maize starch, silica, sodium lauryl sulfate and stearic acid.

What Co-trimoxazole Taj Pharma tablets look like and contents of the pack

Co-trimoxazole Taj Pharma tablets are white, circular, biconvex uncoated tablets.

Pack size:  14, 28, 56, 60, 100, 200 and 300 or 500 tablets.

Not all pack size may be marketed

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com